Premature ejaculation is a debilitating sexual dysfunction. This dysfunction can lead to an inability to enter into, or sustain, relationships and can cause psychological damage to sufferers. Premature ejaculation can also impair reproductive success.
Treatments for premature ejaculation include psychological therapies, topical anesthetics, and the use of devices. All of these treatments have significant drawbacks. Psychological therapies benefit only a subset of patients and require specialized therapists who may not be available to all patients. Furthermore, psychological therapies cannot alleviate premature ejaculation resulting from non-psychological causes. Anesthetic agents decrease sensitivity of tissues, thereby diminishing sexual pleasure. Also, topical anesthetics can be transferred to sexual partners and thereby decrease their sensitivity and pleasure as well. With regard to devices, these can be awkward, inconvenient and embarrassing to use. Devices are highly conspicuous and reveal the very condition which the suffering partner may prefer to conceal. Additionally, devices can cause irritation to one or both partners.
Methods for treating premature ejaculation by systemic administration of some antidepressant compounds (including fluoxetine, sertraline, paroxetine) have been described. See U.S. Pat. Nos. 4,507,323, 4,940,731, 5,151,448, and 5,276,042 and Rosen et al., J. Clin. Psychopharmacol., 19, 67–85 (1999). However, these antidepressants may not be effective for all patients, and their side effects can halt treatment or impair patient compliance. Disease states or adverse interactions with other drugs may contraindicate the use of these compounds or require lower dosages that may not be effective to delay the onset of ejaculation.
U.S. Pat. No. 6,037,360 describes a method of treating premature ejaculation by administration of certain serotonin agonists and antagonists. A serotonin agonist is defined in this patent to be a compound which mimics the effect of serotonin on at least one of its receptors, and a serotonin antagonist is defined to be a compound which blocks the effect of serotonin on at least one of its receptors. Preferred are serotonin 5HT3 receptor antagonists (e.g., ondansetron, ergot alkaloids, granisetron, metoclopramide, trimethobenzamide, tropisetron, dolasetron, batanopride, and zacropride) and serotonin 5HT4 agonists (e.g., cisapride and D-lysergic acid diethylamide). Unfortunately, these compounds have side effects which may contraindicate their use (e.g., ergot alkaloids and D-lysergic acid diethylamide) or have limited effectiveness (e.g., metoclopramide and the like; see PCT application WO 95/13072).
Thus, a need clearly exists for other methods of treating premature ejaculation. In particular, there is a need for a method of treating premature ejaculation that requires no specialized psychological therapy, can be used conveniently and without embarrassment, and does not involve the problems associated with prior therapeutic methods.
Tramadol is a centrally acting synthetic analgesic compound. Its mode of action is not completely understood. From animal tests, at least two complementary mechanisms appear applicable: (1) the binding of the parent compound (tramadol) and the O-demethylated M1 metabolite to μ-opioid receptors; and (2) a weak inhibition of reuptake of norepinephrine and serotonin. Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the M1 metabolite to μ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol.
Apart from analgesia, the use of tramadol to treat frequent urination and urinary incontinence (see U.S. Pat. No. 6,090,856) and to treat coughs, bronchitis and the common cold (see U.S. Pat. Nos. 3,652,589 and 3,830,934) have been described. There is no teaching or suggestion in the prior art that tramadol could be used to delay ejaculation.